It is now well recognized that estrogens and androgens strongly modulate injury in CNS regions completely unrelated to reproductive function or sexual differentiation. These steroids protect (and in restricted conditions, can exacerbate) the neuronal response to injury from ischemic, inflammatory and immunological challenges. The major aim of this program is to 1) dissect important mechanisms by which the principal mammalian estrogen, 17$ estradiol, rescues neurons from experimental stroke, cerebral ischemia and multiple sclerosis and 2) open new territory by understanding the male phenotype of ischemic sensitivity and the role of testosterone in this phenotype. The Program has several important strengths. First, strong investigators with critical expertise have been integrated in the Program. Our preliminary data indicate feasibility of our approaches and demonstrate the potential for significant new knowledge to emerge in the new area of gender-based pathobiology. The investigators are leaders in their fields concerning mechanisms of neuronal function in health and disease. We now sharply focus that expertise on sex and sex steroids, a topic traditionally found of interest only to endocrinology and reproductive medicine. Second, the investigators use sophisticated experimental approaches to evaluate mechanism-oriented hypotheses. Finally, this program is highly novel, one of few to seek out how sex steroids interact with generalized cell death/survival pathways. Instead of minimizing or excluding sex and sex steroids as is commonly done in translational research, the present experimental approach maximizes them. Our findings will elucidate the mechanisms behind a most fundamental "genetic" aspect of disease: biological sex. The Program consists of 3 projects :!) Role of Cocaine Amphetamine Regulated Transcript (CART) in Estrogen mediated Neuroprotection, 2) Testosterone and Cerebral Ischemia, 3) Neuroprotective effects of estrogen and testosterone in experimental autoimmune encephalomyelitis (EAE). These projects are supported by 3 core facilities: 1) Administration;2) Tissue Analysis and 3) Animal Models.